Cu(II) complexes with a salicylaldehyde derivative and α-diimines as co-ligands: synthesis, characterization, biological activity. Experimental and theoretical approach.

Copper(II) complexes with an α-diimine show a wide variety of biological activities, such as antibacterial, antifungal, antioxidant and anticancer. In this work, we synthesized and structurally characterized two novel Cu(II) complexes with methyl 3-formyl-4-hydroxybenzoate (HL) and α-diimines: 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen). Crystal structure analysis shows that the formulas of the compounds are [Cu(bipy)(L)(BF4)] (1) and [Cu(phen)(L)(H2O)](BF4)·H2O (2), with BF4- as a ligand in complex 1, which is rarely coordinated to metals. Both complexes have a square pyramidal geometry, while DFT calculations showed that the most stable structures of complexes 1 and 2 in a water/DMSO mixture are square-planar derivatives [Cu(bipy)(L)]+ and [Cu(phen)(L)]+. The antibacterial activity of compounds was evaluated in vitro on four Gram-negative and four Gram-positive bacterial strains. Complex 2 showed greater antibacterial activity towards all bacterial strains comparable to the control compound Amikacin. Complex 2 exerted a strong cytotoxic effect against the tested cancer cell lines (IC50 values ranging from 0.32 to 0.44 µM). Both complexes caused apoptotic cell death in HeLa cells and a noticeable in vitro antiangiogenic effect. In the concentration range of 5 to 100 µM, the complexes showed the absence of a genotoxic effect and displayed a protective effect against oxidative DNA damage induced by H2O2 in human peripheral blood cells. The interaction between the compounds and calf-thymus DNA was evaluated by diverse techniques suggesting a tight binding, which was also confirmed by molecular docking. In addition, it was found that the complexes bind tightly and reversibly to bovine and human serum albumin.

Iron(III) Complexes with Non-Steroidal Anti-Inflammatory Drugs: Structure, Antioxidant and Anticholinergic Activity, and Interaction with Biomolecules.

One the main research goals of bioinorganic chemists is the synthesis of novel coordination compounds possessing biological potency. Within this context, three novel iron(III) complexes with the non-steroidal anti-inflammatory drugs diflunisal and diclofenac in the presence or absence of the nitrogen donors 1,10-phenanthroline or pyridine were isolated and characterized by diverse techniques. The complexes were evaluated for their ability to scavenge in vitro free radicals such as hydroxyl, 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals, revealing their selective potency towards hydroxyl radicals. The in vitro inhibitory activity of the complexes towards the enzymes acetylcholinesterase and butyrylcholinesterase was evaluated, and their potential to achieve neuroprotection appeared promising. The interaction of the complexes with calf-thymus DNA was examined in vitro, revealing their ability to intercalate in-between DNA nucleobases. The affinity of the complexes for serum albumins was evaluated in vitro and revealed their tight and reversible binding.

Copper(II) complexes with 4-(diethylamino)salicylaldehyde and α-diimines: Anticancer, antioxidant, antigenotoxic effects and interaction with DNA and albumins.

In this article, cytotoxicity, the mechanisms of cytotoxic activity, genotoxicity, and interaction with DNA and proteins, of two Cu(II) complexes with a salicylaldehyde derivative (4-(diethylamino)salicylaldehyde) and α-diimine (2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen)) are reported. Both Cu(II) complexes performed cytotoxic effects against all tested malignant cell lines. Complexes exerted highest cytotoxicity against HeLa and A375 malignant cell lines. The cytotoxic activity of Cu(II) complex with phen as a α-diimine co-ligand was significantly higher in comparison with cytotoxic activity of Cu(II) complex with bipy. Pretreatment with specific inhibitors of caspase-3, caspase-8 or caspase-9, in order to clear up the mode of cell death triggered by two Cu(II) complexes in HeLa cells, indicated the ability of these complexes to induce apoptosis through activation of target caspases. Cu(II)-phen complex exhibited significant antioxidant activity compared with Cu(II)-bipy complex, and showed a better effect on reducing intracellular ROS levels in HeLa cells. Tested complexes did not display genotoxic potential in human peripheral blood leucocytes, but exhibited an antigenotoxic effect in post-treatment, after H2O2 exposure. The study of the in vitro biological properties regarding their affinity towards CT (calf-thymus) DNA and serum albumins showed that the compounds can intercalate to CT DNA, and bind reversibly and tightly to the albumins. Molecular docking studies of the ability of compounds to bind to biomacromolecules are consistent with in vitro studies.

Trinuclear and tetranuclear iron(III) complexes with fenamates: Structure and biological profile.

The interaction of FeCl3 with the fenamate non-steroidal anti-inflammatory drugs has led to the formation and isolation of trinuclear iron(III) complexes, while in the presence of the nitrogen-donors 2,2'-bipyridine or pyridine tetranuclear iron(III) complexes were derived. The five resultant complexes were characterized by diverse techniques (including infrared, electronic and Mössbauer spectroscopy) and their crystal structures were determined by single-crystal X-ray crystallography. These complexes are the first structurally characterized Fe(III)-fenamato complexes. The complexes were evaluated for their ability to scavenge in vitro free radicals such as hydroxyl, 1,1-diphenyl-2-picrylhydrazyl and 2,2΄-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid). The in vitro binding affinity of the complexes to calf-thymus (CT) DNA was examined and their interaction with serum albumins was also investigated. In total, the complexes present promising activity against the radicals tested, and they may bind tightly to CT DNA possibly via intercalation and reversibly to serum albumins.

Manganese(II) coordination compounds of carboxylate non-steroidal anti-inflammatory drugs.

Upon the interaction of MnCl2 with the non-steroidal anti-inflammatory drugs oxaprozin or flufenamic acid in the presence of the nitrogen-donors 2,2'-bipyridine or 1,10-phenanthroline as co-ligands, one dinuclear and two trinuclear Mn(II) complexes were isolated. The complexes were characterized by diverse techniques. The complexes were evaluated for their scavenging activity against free radicals such as hydroxyl, 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid). The in vitro binding affinity of the complexes to calf-thymus (CT) DNA and serum albumins was also monitored. In total, we may suggest that the complexes present promising scavenging activity against the radicals tested, and they may bind to CT DNA via intercalation and reversibly to serum albumins.

Biological evaluation of cobalt(II) complexes with non-steroidal anti-inflammatory drug naproxen.

Cobalt(II) complexes with the non-steroidal anti-inflammatory drug naproxen in the presence or absence of nitrogen-donor heterocyclic ligands (pyridine, 2,2'-bipyridine or 1,10-phenanthroline) have been synthesized and characterized with physicochemical and spectroscopic techniques. The deprotonated naproxen acts as monodentate ligand coordinated to Co(II) ion through a carboxylato oxygen. The crystal structure of [bis(aqua)bis(naproxenato)bis(pyridine)cobalt(II)], 2 has been determined by X-ray crystallography. The EPR spectrum of complex 2 in frozen solution reveals that it retains its structure. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA and [(2,2'-bipyridine)bis(methanol)bis(naproxenato)cobalt(II)] exhibits the highest binding constant to CT DNA. The cyclic voltammograms of the complexes recorded in DMSO solution and in the presence of CT DNA in 1/2 DMSO/buffer (containing 150 mM NaCl and 15 mM trisodium citrate at pH 7.0) solution have shown that they can bind to CT DNA by the intercalative binding mode which has also been verified by DNA solution viscosity measurements. Competitive study with ethidium bromide (EB) has shown that the complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB. Naproxen and its cobalt(II) complexes exhibit good binding propensity to human or bovine serum albumin proteins having relatively high binding constant values. The antioxidant activity of the compounds has been evaluated indicating their high scavenging activity against hydroxyl free radicals and superoxide radicals.

Non-steroidal antiinflammatory drug-copper(II) complexes: structure and biological perspectives.

Copper(II) complexes with the non-steroidal antiinflammatory drug mefenamic acid in the presence of aqua or nitrogen donor heterocyclic ligands (2,2'-bipyridine, 1,10-phenanthroline, 2,2'-bipyridylamine or pyridine) have been synthesized and characterized. The crystal structures of [(2,2'-bipyridine)bis(mefenamato)copper(II)], 2, [(2,2'-bipyridylamine)bis(mefenamato)copper(II)], 4, and [bis(pyridine)bis(methanol)bis(mefenamato)copper(II)], 5, have been determined by X-ray crystallography. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA and [bis(aqua)tetrakis(mefenamato)dicopper(II)] exhibits the highest binding constant to CT DNA. The cyclic voltammograms of the complexes in the presence of CT DNA solution have shown that the complexes can bind to CT DNA by the intercalative binding mode verified also by DNA solution viscosity measurements. Competitive studies with ethidium bromide (EB) indicate that the complexes can displace the DNA-bound EB suggesting strong competition with EB. Mefenamic acid and its complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. All the compounds have been tested for their antioxidant and free radical scavenging activity as well as for their in vitro inhibitory activity against soybean lipoxygenase showing significant activity.

Interaction of copper(II) with the non-steroidal anti-inflammatory drugs naproxen and diclofenac: synthesis, structure, DNA- and albumin-binding.

Copper(II) complexes with the non-steroidal anti-inflammatory drugs (NSAIDs) naproxen and diclofenac have been synthesized and characterized in the presence of nitrogen donor heterocyclic ligands (2,2'-bipyridine, 1,10-phenanthroline or pyridine). Naproxen and diclofenac act as deprotonated ligands coordinated to Cu(II) ion through carboxylato oxygens. The crystal structures of (2,2'-bipyridine)bis(naproxenato)copper(II), 1, (1,10-phenanthroline)bis(naproxenato)copper(II), 2 and bis(pyridine)bis(diclofenac)copper(II), 4 have been determined by X-ray crystallography. The UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA with (2,2'-bipyridine)bis(naproxenato)copper(II) exhibiting the highest binding constant to CT DNA. Competitive study with ethidium bromide (EB) indicates that the complexes can displace the DNA-bound EB suggesting strong competition with EB. The cyclic voltammograms of the complexes recorded in the presence of CT DNA have shown that the complexes can bind to CT DNA by the intercalative binding mode which has also been verified by DNA solution viscosity measurements. The NSAID ligands and their complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. The biological properties of the previously reported complexes [Cu(2)(naproxenato)(4)(H(2)O)(2)], [Cu(2)(diclofenac)(4)(H(2)O)(2)] and [Cu(naproxenato)(2)(pyridine)(2)(H(2)O)] have been also evaluated. The dinuclear complexes exhibit similar affinity for CT DNA as the 2,2'-bipyridine or 1,10-phenanthroline containing complexes. The pyridine containing complexes exhibit the lowest affinity for CT DNA and the lowest ability to displace EB from its EB-DNA complex.

Biological evaluation of non-steroidal anti-inflammatory drugs-cobalt(II) complexes.

Cobalt(II) complexes with the non-steroidal anti-inflammatory drug mefenamic acid in the presence or absence of nitrogen donor heterocyclic ligands (2,2'-bipyridine, 1,10-phenanthroline or pyridine) have been synthesized and characterized with physicochemical and spectroscopic techniques. The experimental data suggest that mefenamic acid acts as deprotonated monodentate ligand coordinated to Co(II) ion through a carboxylato oxygen. The crystal structures of tetrakis(methanol)bis-(mefenamato)cobalt(II), 1 and (2,2'-bipyridine)bis(methanol)bis(mefenamato)cobalt(II), 2 have been determined by X-ray crystallography. The EPR spectra of complexes 1 and 2 in frozen solution reveal that they retain their structures. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA and bis(methanol)bis(pyridine)bis-(mefenamato)cobalt(II) exhibits the highest binding constant. Competitive study with ethidium bromide (EB) has shown that the complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB. The cyclic voltammograms of the complexes recorded in dmso solution and in the presence of CT DNA in 1 : 2 dmso : buffer (containing 150 mM NaCl and 15 mM trisodium citrate at pH 7.0) solution have shown that they can bind to CT DNA by the intercalative binding mode. Mefenamic acid and its cobalt(II) complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. The antioxidant activity of the compounds has been evaluated indicating their high scavenging activity against hydroxyl free radicals and superoxide radicals.